Ricin is one of the most toxic biological agents known. The proposal will test the hypothesis that the mannose receptor (MR), a C-type lectin normally assumed to function in innate immunity, mediates the uptake of ricin into macrophages in the liver and spleen, and thereby initiates the inflammation and cell death responsible for the earliest and most severe affects associated with ricin poisoning. The hypothesis will be tested using MR knock- out (MR-/-) mice, in conjunction with well-established ricin lethal dose challenge protocols. To determine the effect of the MR in the toxicity of ricin in vivo, Specific Aim 1 will compare the median lethal dose of ricin in wild type and MR-/- mice. Specific Aim 2 will determine the contribution of the MR in clearing ricin from the serum, and targeting the toxin to the liver and spleen. Finally, Specific Aim 3 will identify the role of the MR in mediating toxin-induced apoptosis and inflammation in the spleen and liver. This study is expected to uncover fundamental mechanisms by which pathogenic agents such as ricin toxin exploit the MR to bypass normal host defense mechanisms and gain entry into select sub-populations of host cells. This study will also provide critical information necessary to develop inhibitors of ricin that interfere with the earliest steps in the intoxication process, and will, therefore, advance NIAID's mission to develop effective countermeasures against the Category B Select Agents and Toxins. PUBLIC HEALTH RELEVANCE: Ricin is a deadly toxin that is considered a potential bioterrorism agent by the Centers for Diseases Control and the National Institutes of Heath. This study proposes to investigate how ricin toxin enters into cells and causes disease. The results of this study are expected to yield new insights the design of an effective antidote against this deadly toxin.